Abstract P2-20-10: Prognostic impact of lymphocyte-Activation Gene-3 (LAG-3) expression in triple negative breast cancer
Authors: ji-Yeon Kim, Jeehyun Kim, Hae Hyun Jung, eun Yoon Cho, Yeon Hee Park, Jin Seok Ahn, Kyoung-Mee Kim, Young-Hyuck Im
Journal: Cancer Research (2023)

Abstract Introduction Recent advances in breast cancer treatment strategies have improved survival outcomes in metastatic breast cancer (mBC). Targeting immune checkpoint, especially programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1), has made a breakthrough in treating advanced malignancies including breast cancer. Immune checkpoint inhibitors (ICIs), such as pembrolizumab and atezolizumab, in combination with chemotherapy have prolonged survival outcomes in mBC with triple negative subtype. However, the low response rate and resistance of ICIs with anti-PD 1/PDL-1 antibodies is a major limitation and a challenge. Lymphocyte Activation Gene-3 (LAG3; CD223) is a potential cancer immunotherapeutic target due to its negative regulatory role on T cells and cytokines, thereby ensuring immune homeostasis. Several studies suggested that combination immunotherapy of anti-LAG-3 and anti-PD-1 has shown promising efficacy in fighting PD-1 resistance. Therefore, we evaluated the prognostic role of LAG3 in metastatic TNBC (mTNBC) treated with ICIs to figure out resistance mechanism of ICIs. Methods mTNBC patients with available archival tumor tissues, who has received ICIs in Samsung Medical Center, were enrolled in this study. For the evaluation of LAG3 expression in tumor microenvironment, Vectra Polaris Multispectral Imaging and Whole Slide Scanning technique (PerkinElmer, Inc. Hopkinton, MA) was used. Results In total, 64 mTNBC patients were treated with ICI’s with or without cytotoxic chemotherapy between 2019.02- 2021.11. Of 70 mTNBC patients, 41 patients had archival tissues and finally 40 patients were included in this study. Median age was 43.0 years of age (range: 24.5 ~ 64.5). Recurrent mTNBC was 92.5% and only 7.5% was de novo mTNBC. Geremline BRCA1 pathogenic variants were detected in 4 (10.0%) patients. Among 37 recurrent mTNBC patients, 72.5% were treated with neoadjuvant chemotherapy with anthracycline (97.3%) and taxane(97.3%). Among ICI’s, 52.5% were treated with pembrolizumab and 47.5% of atezolizumab. LAG3 expression varies among mTNBC tissues (median cell density: 366, range: 48, 2861 cells/mm2). Among cells expressing LAG3, LAG3 was expressed more in CK+ cells compared with CK- cells (median:150 (20, 2503) cells/mm2 in CK+ cells, median: 88 (2, 806) cells/mm2 in CK- cells, p=0.005). Patients with high LAG3 expression in CK+ cells showed short progression free survival(PFS) compared to those with low LAG3 expression in CK+ cells (median PFS of high vs. low LAG3 expression [months]:1.9 vs. 4.2, p=0.01). On the contrary, patients with high LAG3 expression in CK- cells had 9.1 months of PFS compared to 3.1 months of PFS in patients with low LAG3 expression in CK- cells (p=0.10). In addition, patients with high LAG3 in CK- cells had longer overall survival(OS) compared to those with low LAG3 expression in CK- cells (median OS of high vs. low LAG3 expression [months]: not reached, 15.7, p=0.05). Conclusion LAG3 expression was associated with PFS in patients with mTNBC treated with ICI’s independent of PDL-1 expression. And the prognostic significance of LAG3 expression was different between CK+ cells and CK- cells. These findings need to be proved in large scale clinical trials. Citation Format: ji-Yeon Kim, Jeehyun Kim, Hae Hyun Jung, eun Yoon Cho, Yeon Hee Park, Jin Seok Ahn, Kyoung-Mee Kim, Young-Hyuck Im. Prognostic impact of lymphocyte-Activation Gene-3 (LAG-3) expression in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-10.